We are studying the normal differentiation and regulatory interactions of B cells, T cells and NK cells to gain information that can be used to analyze lymphoid malignancies, immunodeficiency diseases and other disorders of immunoregulation. A large panel of monoclonal antibodies has been prepared against B cell determinants including antibodies to Ig heavy and light chain isotypes, allotypes and idiotypes and VH subgroups, as well as non-Ig determinants. These have been used to define the genesis of pre-B and B cells in fetal liver and bone marrow, and their subsequent migration and differentiation in peripheral lymphoid tissues. Ig isotype switching has been studied in leukemic pre-B cell clones, newborn mouse liver in culture and normal human B cells. Our studies suggest that isotype switching is nonrandom, non-T cell dependent and usually involves direct switches from IgM to other isotypes; i.e., sequential isotype switching appears uncommon. Isotype-committed B cells were found to be selectively induced by helper T cells or soluble factors. Studies of human B cell and plasma cell malignancies suggest that clonal involvement in each case occurs prior to isotype switching. Children with pre-B leukemia were shown to have a significantly poorer prognosis than children with "null" cell leukemia. A VH idiotype-related determinant has been identified on a small subset of T cells. This T-cell receptor candidate is a glycoprotein distinct from H-2, Thy-1 and Lyt molecules. A monoclonal antibody, HNK-1 or Leu 7, was prepared against a cell surface molecule of 110 Kd which is selectively expressed by human NK cells. It has been used to examine the development, distribution and function of NK cells and to define functionally deficient NK cells in patients with Chediak-\ Higashi syndrome and AIDS. Hemophilia patients treated with Factor VIII concentrates were found to have an isolated increase in circulating T suppressor cells.